Melatonin and bone-related diseases: an updated mechanistic overview of current evidence and future prospects.

PURPOSE: Bone diseases account for an enormous cost burden on health systems. Bone disorders are considered as age-dependent diseases. The aging of world population has encouraged scientists to further explore the most effective preventive modalities and therapeutic strategies to overcome and reduce the high cost of bone disorders. Herein, we review the current evidence of melatonin's therapeutic effects on bone-related diseases. METHODS: This review summarized evidences from in vitro, in vivo, and clinical studies regarding the effects of melatonin on bone-related diseases, with a focus on the molecular mechanisms. Electronically, Scopus and MEDLINE®/PubMed databases were searched for articles published on melatonin and bone-related diseases from inception to June 2023. RESULTS: The findings demonstrated that melatonin has beneficial effect in bone- and cartilage-related disorders such as osteoporosis, bone fracture healing, osteoarthritis, and rheumatoid arthritis, in addition to the control of sleep and circadian rhythms. CONCLUSION: A number of animal and clinical studies have indicated that various biological effects of melatonin may suggest this molecule as an effective therapeutic agent for controlling, diminishing, or suppressing bone-related disorders. Therefore, further clinical studies are required to clarify whether melatonin can be effective in patients with bone-related diseases.

Clinical Application of Melatonin in the Treatment of Cardiovascular Diseases: Current Evidence and New Insights into the Cardioprotective and Cardiotherapeutic Properties.

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, tending to happen in younger individuals in developed countries. Despite improvements in medical treatments, the therapy and long-term prognosis of CVDs such as myocardial ischemia-reperfusion, atherosclerosis, heart failure, cardiac hypertrophy and remodeling, cardiomyopathy, coronary artery disease, myocardial infarction, and other CVDs threatening human life are not satisfactory enough. Therefore, many researchers are attempting to identify novel potential therapeutic methods for the treatment of CVDs. Melatonin is an anti-inflammatory and antioxidant agent with a wide range of therapeutic properties. Recently, several investigations have been carried out to evaluate its effectiveness and efficiency in CVDs therapy, focusing on mechanistic pathways. Herein, this review aims to summarize current findings of melatonin treatment for CVDs.

Nurses' recovery experiences during the COVID-19 pandemic in Isfahan, Iran: A qualitative study.

AIM: The aim of this study is to explore and describe the recovery experiences of nurses working in COVID-19 wards. BACKGROUND: The global outbreak of coronavirus in 2020 has extracted job stress for nurses. Job stress has impacts on physical and mental health and performance, so recovery is essential to restore the lost energy resources. METHOD: Semi-structured interviews were conducted with 12 nurses in Isfahan city of Iran. RESULTS: The research results were extracted as 5 main themes, 14 subthemes and 54 items. The main themes are detachment from work, relaxation, non-work activities, affiliation and meaning. The combination of these themes led to the clear statement that using recovery experiences is a major step toward relieving the nurses' COVID-19-related stress and their physical and mental resuscitation. CONCLUSION: The use of recovery experiences, including detachment from work, relaxation, non-work activities, affiliation and meaning by nurses, helps them cope with job stressors and regain their resources. IMPLICATIONS FOR NURSING MANAGEMENT: It is the responsibility of health system policy makers, hospital managers and nurse managers to design and implement training programmes for nurses to use recovery experiences as stress management techniques in their profession.

An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress.

Cancers are serious life-threatening diseases which annually are responsible for millions of deaths across the world. Despite many developments in therapeutic approaches for affected individuals, the rate of morbidity and mortality is high. The survival rate and life quality of cancer patients is still low. In addition, the poor prognosis of patients and side effects of the present treatments underscores that finding novel and effective complementary and alternative therapies is a critical issue. Melatonin is a powerful anticancer agent and its efficiency has been widely documented up to now. Melatonin applies its anticancer abilities through affecting various mechanisms including angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Regarding the implication of mentioned cellular processes in cancer pathogenesis, we aimed to further evaluate the anticancer effects of melatonin via these mechanisms.

The ameliorative effect of ellagic acid on di-(2-ethylhexyl) phthalate-induced testicular structural alterations, oxidative stress, inflammation and sperm damages in adult mice.

BACKGROUND: Phthalates such as di (2-ethylhexyl) phthalate (DEHP) are well known exogenous substances, disrupting reproductive system function and structure. The current research demonstrated the effect of ellagic acid (EA) on DEHP-induced testicular injury in mice. METHODS: Thirty-five healthy adult male mice were randomly divided to five groups; normal saline receiving group, DEHP (2 g/kg/day, dissolved in corn oil, p.o.) receiving group, DEHP (2 g/kg/day, dissolved in corn oil, p.o.) and EA receiving groups (25, 50 and 100 mg/kg/day, p.o.). Treatment duration of animals was 14 days. Body and testes weights and sperm characteristics and histological changes of testes were evaluated. Serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were analyzed. In the testicular tissue, oxidative/nitrosative stress markers and inflammatory cytokine levels were measured. RESULTS: Ellagic acid significantly reduced DEHP-induced reduction of body and testes weights. The DEHP-induced reduction of spermatogonia, primary spermatocyte and sertoli cells numbers as well as reduction of sperm vitality and progressive motility were reversed by EA. Furthermore, EA inhibited DEHP-induced alterations in serum hormone levels. These effects were associated with the reduction of DEHP-induced increased level of oxidative stress and inflammatory responses. CONCLUSIONS: Ellagic acid considerably inhibits testicular toxicity of DEHP through reducing oxidative/nitrosative stress and inflammatory responses. Our data suggest that EA may be considered as a promising agent to inhibit male reproductive toxicity induced by endocrine disrupting chemicals such as DEHP.

Melatonin and neuroblastoma: a novel therapeutic approach.

Neuroblastoma is a deadly and serious malignancy among children. Although many developments have been occurred for the treatment of this disease, the rate of mortality is still high. Therefore, it is necessary to search for novel complementary and alternative therapies. Melatonin, a hormone secreted from pineal gland, is a multifunctional agent having anticancer potentials. Recently, several investigations have been conducted indicating melatonin effects against neuroblastoma. In this paper, we summarize current evidence on anti-neuroblastoma effects of melatonin based on cellular pathways.

Gallic acid ameliorates sodium arsenite-induced renal and hepatic toxicity in rats.

Chronic exposure to toxic inorganic arsenic results in the adverse health effects including skin lesions, cardiovascular diseases, diabetes, neurological disorders, and liver and kidney diseases. Gallic acid (GA) is an important phenolic compound, which could protect different tissues from oxidative stress induced damage. The present study investigated effects of GA against sodium arsenite (SA)-induced renal and hepatic toxicity. Thirty-five rats were randomly divided in to five groups; group 1 was treated with normal saline (2 ml/kg/day, p.o.; for 21 days); group 2 was exposed to SA (10 mg/kg/day, p.o.; for 14 days); groups 3 and 4 were treated with GA (10 and 30 mg/kg/day, respectively; for 7 days) prior to exposure to SA, and treatment was continued up to 21 days in parallel with SA administration; group 5 was treated with GA (30 mg/kg/day, p.o.; for 21 days). The level of MDA, IL-1ß, NO and glutathione (GSH) and the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were evaluated in kidney and liver tissues. Histopathological parameters and serum levels of ALT, AST, ALP, Cr and BUN were also assessed. Treatment with GA remarkably improved SA-induced alteration of hematological and histopathological parameters; these protective effects were associated with the reduction of SA-induced elevation of MDA, IL-1ß and NO levels as well as reduction of GSH level and GPx, SOD and CAT activity. Our results suggest that GA may inhibit SA-induced kidney and liver toxicity through scavenging reactive free radicals and increasing intracellular antioxidant capacity.

Correction to: Melatonin and urological cancers: a new therapeutic approach.

[This corrects the article DOI: 10.1186/s12935-020-01531-1.].

Melatonin and urological cancers: a new therapeutic approach.

Urological cancers are responsible for thousands of cancer-related deaths around the world. Despite all developments in therapeutic approaches for cancer therapy, the absence of efficient treatments is a critical and vital problematic issue for physicians and researchers. Furthermore, routine medical therapies contribute to several undesirable adverse events for patients, reducing life quality and survival time. Therefore, many attempts are needed to explore potent alternative or complementary treatments for great outcomes. Melatonin has multiple beneficial potential effects, including anticancer properties. Melatonin in combination with chemoradiation therapy or even alone could suppress urological cancers through affecting essential cellular pathways. This review discusses current evidence reporting the beneficial effect of melatonin in urological malignancies, including prostate cancer, bladder cancer, and renal cancer.

Therapeutic application of nutraceuticals in diabetic nephropathy: Current evidence and future implications.

Diabetes mellitus (DM) is a common metabolic disease which may cause several complications, such as diabetic nephropathy (DN). The routine medical treatments used for DM are not effective enough and have many undesirable side effects. Moreover, the global increased prevalence of DM makes researchers try to explore potential complementary or alternative treatments. Nutraceuticals, as natural products with pharmaceutical agents, have a wide range of therapeutic properties in various pathologic conditions such as DN. However, the exact underlying mechanisms have not been fully understood. The purpose of this review is to summarize recent findings on the effect of nutraceuticals on DN.

Protective effects of atorvastatin against high glucose-induced nuclear factor-κB activation in cultured C28I2 chondrocytes.

Aims: A number of epidemiological and experimental documents emphasizes a close relation between type 2 diabetes mellitus (T2DM) and the progression of osteoarthritis (OA). In order to understand the underlying mechanisms of atorvastatin (ATO) in OA, we sought to explore the effect of ATO on high glucose (HG)-mediated NF-κB activation in cultured C28I2 chondrocytes. Methods: The effects of various concentrations of ATO on C28I2 human chondrocytes viability were assessed to obtain the non-cytotoxic concentrations of drug by MTT-assay. The cells were pretreated with 0.01 and 0.1 µM ATO for 6 h, followed by incubation with HG (75 mM) for 72 h. The protein expressions of IκBα (np), IκBα (p), NF-κB (p), and NF-κB (np) were analyzed by western blotting. The effects of ATO on the mRNA expressions of chondrogenic specific markers including SOX9, aggrecan, collagen type 2, and COMP were evaluated by reverse transcription-polymerase chain reaction. Results: ATO in determined concentrations had no cytotoxic effect on C28I2 cells after 72 h. ATO pretreatment exerted remarkable protective effects against HG-induced cytotoxicity. Moreover, ATO decreased IκBα phosphorylation and NF-κB nuclear translocation. It was also able to improve the gene expression of chondrogenic-specific markers in C28I2 cells compared to the control group. Conclusion: ATO could significantly decrease HG-induced inflammation in the cultured C28I2 chondrocytes through the activation of canonical NF-κB signaling pathway. These beneficial effects of ATO may be owing to its anti-inflammatory properties. Therefore, treatment with ATO may provide an effective approach to prevent HG-induced cartilage destruction in clinical setting.

Protective effects of gallic acid against methotrexate-induced toxicity in rats.

BACKGROUND: Methotrexate, as a chemotherapy drug, can cause chronic liver damage and oxidative stress. Aim of this study was to evaluate the preventive effect of gallic acid (GA) on methotrexate (MTX)-induced oxidative stress in rat liver. METHODS: Twenty-eight male rats were randomly divided into four groups as control, MTX (20 mg/kg, i.p.), MTX + GA (30 mg/kg/day, orally) and GA treated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. Malondialdehyde (MDA) and glutathione (GSH) levels and hepatic antioxidant enzymes activities including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) were assayed in liver tissue. The expression of SOD2 and GPx1 genes were evaluated by real-time RT-PCR and liver histopathology was evaluated by light microscopy. RESULTS: The result obtained from current study showed that GA remarkably reduced MTX-induced elevation of AST, ALT and ALP and increased MTX-induced reduction in GSH content, GPx, CAT and SOD activity as well as GPx1 and SOD2 gene expressions. Histological results showed that MTX led to liver damage and GA could improve histological changes. CONCLUSIONS: Our results indicate that GA ameliorates biochemical and oxidative stress parameters in the liver of rats exposed to MTX.

Evaluating the Protective Effects and Mechanisms of Diallyl Disulfide on Interlukin-1ß-Induced Oxidative Stress and Mitochondrial Apoptotic Signaling Pathways in Cultured Chondrocytes.

The protective effects and mechanisms of DADS on IL-1ß-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. The effect of various concentrations of DADS (1, 5 10, 25, 50, and 100 µM) on C28I2 cell viability was evaluated in different times (2, 4, 8, 16, and 24 h) to obtain the non-cytotoxic concentrations of drug by MTT-assay. The protective effect of non-toxic concentrations of DADS on experimentally induced oxidative stress and apoptosis by IL-1ß in C28I2 was evaluated. The effects of DADS on IL-1ß-induced intracellular ROS production and lipid peroxidation were detected and the proteins expression of Nrf2, Bax, Bcl-2, caspase-3, total and phosphorylated JNK, and P38 MAPKs were analyzed by Western blotting. The mRNA expression of detoxifying phase II/antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. DADS in 1, 5, 10, and 25 µM concentrations had no cytotoxic effect after 24 h. Pretreatment with DADS remarkably increased Nrf2 nuclear translocation as well as the genes expression of detoxifying phase II/antioxidant enzymes and reduced IL-1ß-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. DADS could considerably reduce IL-1ß-induced oxidative stress and consequent mitochondrial apoptosis, as the major mechanisms of chondrocyte cell death in an experimental model of osteoarthritis. It may be considered as natural product in protecting OA-induced cartilage damage in clinical setting. J. Cell. Biochem. 118: 1879-1888, 2017. © 2017 Wiley Periodicals, Inc.

Protective Effect of Ginger (Zingiber officinale Roscoe) Extract against Oxidative Stress and Mitochondrial Apoptosis Induced by Interleukin-1ß in Cultured Chondrocytes.

AIMS: The protective effects of ginger (Zingiber officinale Roscoe) extract on IL-1ß-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. METHODS: The effects of various concentrations of ginger extract on C28I2 human chondrocyte viability were evaluated in order to obtain noncytotoxic concentrations of the drug by methylthiotetrazole assay. The cells were pretreated with 5 and 25 µg/mL ginger extract for 24 h, followed by incubation with IL-1ß (10 ng/mL) for 24 h. The effects of ginger extract on IL-1ß-induced intracellular reactive oxygen species (ROS) production and lipid peroxidation were examined. The mRNA expressions of antioxidant enzymes including catalase, superoxide dismutase-1, glutathione peroxidase-1, glutathione peroxidase-3, and glutathione peroxidase-4 were evaluated by reverse transcription polymerase chain reaction. The protein expressions of Bax, Bcl-2, and caspase-3 were analyzed by Western blotting. RESULTS: No cytotoxicity was observed at any concentration of ginger extract in C28I2 cells. Ginger extract pretreatment remarkably increased the gene expression of antioxidant enzymes and reduced the IL-1ß-induced elevation of ROS, lipid peroxidation, the Bax/Bcl-2 ratio, and caspase-3 activity. CONCLUSIONS: Ginger extract could considerably reduce IL-1ß-induced oxidative stress and consequent mitochondrial apoptosis as the major mechanisms of chondrocyte cell death. These beneficial effects of ginger extract may be due to its antioxidant properties. It may be considered as a natural herbal product to prevent OA-induced cartilage destruction in the clinical setting.

Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of articular cartilage. As chondrocytes are the only cell type forming the articular cartilage, their gradual loss is the main cause of OA. There is a substantial body of published research that suggests reactive oxygen species (ROS) are major causative factors for chondrocyte damage and OA development. Oxidative stress elicited by ROS is capable of oxidizing and subsequently disrupting cartilage homeostasis, promoting catabolism via induction of cell death and damaging numerous components of the joint. IL-1ß and TNF-α are crucial inflammatory factors that play pivotal roles in the pathogenesis of OA. In this process, the mitochondria are the major source of ROS production in cells, suggesting a role of mitochondrial dysfunction in this type of arthritis. This may also be promoted by inflammatory cytokines such as IL-1ß and TNF-α which contribute to chondrocyte death. In patients with OA, the expression of endoplasmic reticulum (ER) stress-associated molecules is positively correlated with cartilage degeneration. Melatonin and its metabolites are broad-spectrum antioxidants and free radical scavengers which regulate a variety of molecular pathways such as inflammation, proliferation, apoptosis, and metastasis in different pathophysiological situations. Herein, we review the effects of melatonin on OA, focusing on its ability to regulate apoptotic processes and ER and mitochondrial activity. We also evaluate likely protective effects of melatonin on OA pathogenesis.

Melatonin synergistically enhances protective effect of atorvastatin against gentamicin-induced nephrotoxicity in rat kidney.

The risk of serious side-effects such as nephrotoxicity is the principal limitation of gentamicin (GEN) therapeutic efficacy. Oxidative stress is considered to be an important mediator of GEN-induced nephrotoxicity. The present study was designed to evaluate the efficacy of the combination of melatonin (MT) plus atorvastatin (ATO) against GEN-induced nephrotoxicity in rats. We utilized 30 male Wistar albino rats allocated in 5 groups, each containing 6 rats: control, GEN (100 mg/kg/day), ATO (10 mg/kg/day) + GEN, MT (20 mg/kg/day) + GEN, and ATO (10 mg/kg/day) plus MT (20 mg/kg/day) + GEN. Kidney weight, serum creatinine and urea concentration, renal ROS, MDA, GSH levels, SOD, and CAT activity were determined. GEN-induced nephrotoxicity was evidenced by marked elevations in serum urea and creatinine, kidney weight, renal ROS, and MDA levels and reduction in renal GSH level, SOD and CAT activity. MT pretreatment significantly lowered the elevated serum creatinine concentration, kidney weight, renal ROS and MDA levels. However ATO could not reduce these parameters, but similarly to MT, it was able to enhance the renal GSH level, CAT and SOD activity. In addition, a combination therapy of MT plus ATO enhanced the beneficial effects of ATO, while not changing the effects of MT effects or even improving them. The present study indicates that a combination therapy of MT plus ATO can attenuate renal injury in rats treated with GEN, possibly by reducing oxidative stress, and it seems that MT can enhance the beneficial effects of ATO.

Therapeutic Effects of Melatonin in the Regulation of Ferroptosis: A Review of Current Evidence.

Ferroptosis is implicated in the pathogenesis of multiple diseases, including neurodegenerative diseases, cardiovascular diseases, kidney pathologies, ischemia-reperfusion injury, and cancer. The current review article highlights the involvement of ferroptosis in traumatic brain injury, acute kidney damage, ethanol-induced liver injury, and PM2.5-induced lung injury. Melatonin, a molecule produced by the pineal gland and many other organs, is well known for its anti- aging, anti-inflammatory, and anticancer properties and is used in the treatment of different diseases. Melatonin's ability to activate anti-ferroptosis pathways including sirtuin (SIRT)6/p- nuclear factor erythroid 2-related factor 2 (Nrf2), Nrf2/ antioxidant responsive element (ARE)/ heme oxygenase (HO-1)/SLC7A11/glutathione peroxidase (GPX4)/ prostaglandin-endoperoxide synthase 2 (PTGS2), extracellular signal-regulated kinase (ERK)/Nrf2, ferroportin (FPN), Hippo/ Yes-associated protein (YAP), Phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) and SIRT6/ nuclear receptor coactivator 4 (NCOA4)/ ferritin heavy chain 1 (FTH1) signaling pathways suggests that it could serve as a valuable therapeutic agent for preventing cell death associated with ferroptosis in various diseases. Further research is needed to fully understand the precise mechanisms by which melatonin regulates ferroptosis and its potential as a therapeutic target.

Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis.

Fibrosis, the excessive deposition of fibrous connective tissue in an organ in response to injury, is a pathological condition affecting many individuals worldwide. Fibrosis causes the failure of tissue function and is largely irreversible as the disease progresses. Pharmacologic treatment options for organ fibrosis are limited, but studies suggest that antioxidants, particularly melatonin, can aid in preventing and controlling fibrotic damage to the organs. Melatonin, an indole nocturnally released from the pineal gland, is commonly used to regulate circadian and seasonal biological rhythms and is indicated for treating sleep disorders. While it is often effective in treating sleep disorders, melatonin's anti-inflammatory and antioxidant properties also make it a promising molecule for treating other disorders such as organ fibrosis. Melatonin ameliorates the necrotic and apoptotic changes that lead to fibrosis in various organs including the heart, liver, lung, and kidney. Moreover, melatonin reduces the infiltration of inflammatory cells during fibrosis development. This article outlines the protective effects of melatonin against fibrosis, including its safety and potential therapeutic effects. The goal of this article is to provide a summary of data accumulated to date and to encourage further experimentation with melatonin and increase its use as an anti-fibrotic agent in clinical settings.

Melatonin: Current evidence on protective and therapeutic roles in gynecological diseases.

Melatonin, a potent antioxidant and free radical scavenger, has been demonstrated to be effective in gynecological conditions and female reproductive cancers. This review consolidates the accumulating evidence on melatonin's multifaceted protective effects in different pathological contexts. In gynecological conditions such as endometriosis, polycystic ovary syndrome (PCOS), and uterine leiomyoma, melatonin has shown promising effects in reducing oxidative stress, inflammation, and hormonal imbalances. It inhibits adhesion molecules' production, and potentially mitigates leukocyte adherence and inflammatory responses. Melatonin's regulatory effects on hormone production and insulin sensitivity in PCOS individuals make it a promising candidate for improving oocyte quality and menstrual irregularities. Moreover, melatonin exhibits significant antitumor effects by modulating various signaling pathways, promoting apoptosis, and suppressing metastasis in breast cancers and gynecological cancers, including ovarian, endometrial, and cervical cancers. Furthermore, melatonin's protective effects are suggested to be mediated by interactions with its receptors, estrogen receptors and other nuclear receptors. The regulation of clock-related genes and circadian clock systems may also contribute to its inhibitory effects on cancer cell growth. However, more comprehensive research is warranted to fully elucidate the underlying molecular mechanisms and establish melatonin as a potential therapeutic agent for these conditions.

Significant Interaction between Melatonin and Titanium Bone Implants: Available Evidence and Future Research Directions.

The trend in the incidence rate of bone fractures has been upward and as a result, the burden associated with orthopedic fractures has increased significantly. Titanium (Ti) implants are considered a preferred method of managing long bone fractures. However, no benefit comes without some downside, and using Ti implants is associated with several complications. In this respect, it was observed that in bones, Ti can disrupt the bone healing process by disturbing the balance of osteoclast and osteoblast activation and also increasing the production of inflammatory cytokines. Melatonin is a widely-acting molecule that possesses strong anti-oxidant features. This molecule reinforces mineral density and improves bone formation processes. In this review, we focused on the protective effect of melatonin in mitigating the Ti-related complications.